Synthesis and In Vitro Antitumor Effect of New Vindoline-steroid Hybrids

Keglevich, András; Zsiros, Vivian; Keglevich, Péter; Szigetvári, Áron; Dékány, Miklós; Szántay, Csaba; Mernyák, Erzsébet; Wölfling, János; Hazai, László

doi:10.2174/1385272823666190614113218

Cited by 8 publications

(10 citation statements)

References 22 publications

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“…The organic phase was dried over MgSO 4 , then the solvent evaporated under reduced pressure. After preparative TLC (dichloromethane-methanol = 15:1) 47 mg (36%) of a pale yellow crystalline product (24) 17-(4-Bromobutanoyloxy)vindoline (22) [22,23] (180 mg, 0.32 mmol) was dissolved in 8 mL of anhydrous DCM, and the stirring was started under argon. Then, 0,072 mL (0.64 mmol) of N-methylpiperazine was added.…”

Section: Synthesis Of 10-(3-carboxypropanamido)vindoline (6)mentioning

confidence: 99%

“…Recently, several experiments were performed to conjugate Vinca alkaloids with different types of amino acid esters, steroids and triphenylphosphine [19][20][21][22][23][24]. The advantage of linking with amino acids is that the given products, bound to carrier peptides (e.g., octaarginine), are able to enter directly into the cancer cells, thereby enabling more targeted therapy, and thus reducing the mentioned serious side effects.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, it has antitumor activity on its own [25]. The products obtained showed promising half maximal inhibitory concentration (IC 50 ) values [19][20][21], or were measured across the entire NCI cell panel and had promising in vitro cytotoxic activities (in terms of growth percent rates (GPR) and growth inhibition of 50% of cells (GI 50 ) values) [22][23][24], according to the National Institutes of Health (NIH), US [26][27][28][29]. The amino acid-conjugated vindoline derivatives (7 and 8) that we aimed at were achieved after the synthesis of 10-aminovindoline (5), known in the literature [30] (Scheme 1).…”

Section: Introductionmentioning

confidence: 99%

“…The expected products (7 and 8) were obtained in yields of 63% and 27%, respectively. promising in vitro cytotoxic activities (in terms of growth percent rates (GPR) and growth inhibition of 50% of cells (GI50) values) [22][23][24], according to the National Institutes of Health (NIH), US [26][27][28][29].…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Cytotoxic Activity of New Vindoline Derivatives Coupled to Natural and Synthetic Pharmacophores

et al. 2020

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New Vinca alkaloid derivatives were synthesized to improve the biological activity of the natural alkaloid vindoline. To this end, experiments were performed to link vindoline with various structural units, such as amino acids, a 1,2,3-triazole derivative, morpholine, piperazine and N-methylpiperazine. The structure of the new compounds was characterized by NMR spectroscopy and mass spectrometry (MS). Several compounds exhibited in vitro antiproliferative activity against human gynecological cancer cell lines with IC50 values in the low micromolar concentration range.

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Section: Synthesis Of 10-(3-carboxypropanamido)vindoline (6)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synthesis and Cytotoxic Activity of New Vindoline Derivatives Coupled to Natural and Synthetic Pharmacophores

et al. 2020

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“…Accordingly, 5α-dihydrotestosterone and 19-nortestosterone were connected to vindoline (1) in positions 10 and 17 through succinate linkers. From the successfully synthesized four new hybrid derivatives, the most efficient one was compound 18, where 19-nortestosterone was coupled with vindoline (1) in position 17 ( Figure 6) [28]. According to the in vitro biologic evaluations of NIH (USA), compound 18 displayed increased cell growth inhibition than vindoline (1), furthermore, it showed a higher antitumor effect on several cell lines even than vinblastine (3) sulfate used in therapy.…”

Section: Vinca Hybrid Molecules Containing Steroid Vectorsmentioning

confidence: 99%

Results in Chemistry of Natural Organic Compounds. Synthesis of New Anticancer Vinca Alkaloids and Flavone Alkaloids

et al. 2020

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The antitumor indole–indoline alkaloids of the evergreen Catharanthus roseus—namely vinblastine and vincristine—are widely used in chemotherapy of cancer. Many efforts were made to synthesize more efficient derivatives with less side-effect. The 14,15-cyclopropane derivative of vinblastine was synthesized successfully by a five-step procedure starting from vindoline. Vincristine, vinorelbine and several derivatives condensed with a cyclopropane ring were synthesized. Various hybrid molecules were prepared by the coupling reaction of vindoline and methyl ester of tryptophan, which were conjugated by carrier peptides of octaarginine. Studying the halogenation reactions of vindoline and catharanthine some fluorine derivatives were obtained which showed promising antitumor activity on various tumor types. The synthesis of the Aspidospermane alkaloid bannucine and 5′-epibannucine were carried out using N-acyliminium intermediates. The same intermediate was also applied in the first synthesis of sessiline. The research group have synthesized of flavonoid alkaloids: dracocephins A and B. Further three flavonoid alkaloids, namely 8-(2”-pyrrolidinon-5′′-yl)quercetin, 6-(2′′-pyrrolidinon-5′′-yl)-(−)- and 8-(2′′-pyrrolidinon-5′′-yl)-(−)-epicatechin were prepared by acid-catalyzed regioselective Mannich reaction starting from the corresponding flavonoid precursor. Vindoline was also coupled to synthetic pharmacophores, such as triphenylphosphine and various N-heterocycles. Some of these hybrid molecules showed significant antitumor activity. Furthermore, 7-OH and 7-NH modified flavonoid derivatives were synthesized by a regioselective alkylation followed by Smiles rearrangement and hydrolysis.

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Synthesis of Novel Vindoline‐Chrysin Hybrids

Mayer

Nagy

Keglevich

et al. 2021

Chemistry & Biodiversity

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Vinca alkaloids are well-known microtubule targeting agents, which are used against some types of cancer. Vindoline is one of the monomeric Vinca alkaloids which does not have anti-tumor effect, although its derivatives have serious impact on the field of these indole alkaloids. Chrysin is a secondary plant metabolite, which has broad-spectrum biological activity, among others anticancer activity. Chrysin had shown synergic effect with several antiproliferative compounds (e. g., doxorubicin, cisplatin and ciglitazone), therefore, we attempted the synthesis of a novel vindoline-chrysin hybrid molecule. However, in the first case a diphenylamine structure was isolated. The mechanism of the unexpected reaction was studied, and then the originally targeted hybrid was synthesized by a reverse route coupling. A further hybrid was produced using a different site of the molecule. The antitumor activities were determined against 60 human tumor cell lines (NCI60), where the aimed hybrid showed low micromolar GI 50 values on most of the cell lines.

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Synthesis and In Vitro Antitumor Effect of New Vindoline-steroid Hybrids

Cited by 8 publications

References 22 publications

Synthesis and Cytotoxic Activity of New Vindoline Derivatives Coupled to Natural and Synthetic Pharmacophores

Synthesis and Cytotoxic Activity of New Vindoline Derivatives Coupled to Natural and Synthetic Pharmacophores

Results in Chemistry of Natural Organic Compounds. Synthesis of New Anticancer Vinca Alkaloids and Flavone Alkaloids

Synthesis of Novel Vindoline‐Chrysin Hybrids

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